The present invention relates to particular salts of an integrin receptor antagonist. More particularly, the invention relates to amine salts of 3-(2-methyl-pyrimidin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoic acid, which are potent integrin xcex1vxcex23 receptor antagonists. These novel salts are therefore useful for the treatment and prevention of diseases and conditions for which an antagonist of the integrin xcex1vxcex23 receptor is indicated.
Integrin xcex1vxcex23 receptor antagonists have been described as being of use for the prevention and/or treatment of osteoporosis, vascular restenosis, macular degeneration, diabetic retinopathy, atherosclerosis, inflammatory arthritis, cancer, and metastatic tumor growth [see, for example, M. E. Duggan, et al., xe2x80x9dLigands to the integrin receptor xcex1vxcex23, Exp. Opin. Ther. Patents, 10: 1367-1383 (2000); M. Gowen, et al., xe2x80x9cEmerging therapies for osteoporosis,xe2x80x9d Emerging Drugs, 5: 1-43 (2000); J. S. Kerr, et al., xe2x80x9cSmall molecule xcex1v integrin antagonists: novel anticancer agents,xe2x80x9d Exp. Opin. Invest. Drugs, 9: 1271-1291 (2000); and W. H. Miller, et al., xe2x80x9cIdentification and in vivo efficacy of small-molecule antagonists of integrin xcex1vxcex23 (the vitronectin receptor),xe2x80x9d Drug Discovery Today, 5: 397-408 (2000)].
U.S. Pat. No. 6,048,861, assigned to Merck and Co., describes a class of 9-substituted-3-aryl-nonanoic acid derivatives, which are potent integrin xcex1vxcex23 receptor antagonists and therefore useful for inhibiting bone resorption, vascular restenosis, treating and/or preventing osteoporosis, and inhibiting diseases and conditions associated with excessive and undesirable angiogenesis. Specifically disclosed in U.S. Pat. No. 6,048,861 is 3-(2-methyl-pyrimidin-5-yl)-9-(5,6,7,8-tetrahydro-[1, 8]-naphthyridin-2-yl)-nonanoic acid. Pharmaceutically acceptable salts of this compound are generically encompassed within the scope of U.S. Pat. No. 6,048,861.
However, there is no specific disclosure in the above reference of the newly discovered amine salts of 3-(2-methyl-pyrimidin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoic acid of structural formula I below.
This invention provides new amine salts of 3-(2-methyl-pyrimidin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoic acid of the following structural formula I: 
or a pharmaceutically acceptable solvate, including hydrate, thereof, wherein
R1 and R2 are both hydrogen,
R1 is hydrogen and R2 is C(CH2OH)3,
R1 is hydrogen and R2 is C(CH3)2CH2OH,
R1 is hydrogen and R2 is CH2CH2NH2, or
R1 is CH2C6H5 and R2 is CH2CH2C6H5.
The amine salts of the present invention have a chiral center (indicated with an *) at the C-3 position of the nonanoic acid chain and can thus occur as a racemate, racemic mixture, and single enantiomers, with all isomeric forms being included in the present invention. The separate enantiomers, substantially free of the other, are included within the scope of the invention, as well as mixtures of the two enantiomers.
Therefore, one embodiment of the present invention provides the amine salts of 3(S)-(2-methyl-pyrimidin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoic acid of structural formula II: 
wherein
R1 and R2 are both hydrogen,
R1 is hydrogen and R2 is C(CH2OH)3,
R1 is hydrogen and R2 is C(CH3)2CH2OH,
R1 is hydrogen and R2 is CH2CH2NH2, or
R1 is CH2C6H5 and R2 is CH2CH2C6H5.
A second embodiment of the present invention provides the amine salts of 3(R)-(2-methyl-pyrimidin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoic acid of structural formula III: 
wherein
R1 and R2 are both hydrogen,
R1 is hydrogen and R2 is C(CH2OH)3,
R1 is hydrogen and R2 is C(CH3)2CH2OH,
R1 is hydrogen and R2 is CH2CH2NH2, or
R1 is CH2C6H5 and R2 is CH2CH2C6H5.
More specifically, the amine salts of the present invention are comprised of one molar equivalent of 3-(2-methyl-pyrimidin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoic acid anion and one molar equivalent of ammonium (R1=R2=H) cation, protonated ethylenediamine cation (R1=H, R2=CH2CH2NH2), protonated 2-amino-2-methyl-1-propanol cation [R1=hydrogen, R2=C(CH3)2CH2OH], protonated tris(hydroxymethyl)aminomethane cation [R1 =hydrogen, R2=C(CH2OH)3], or protonated N-benzyl-2-phenethylamine cation (R1=CH2C6H5, R2=CH2CH2C6H5).
In a further embodiment of the present invention, the amine salts of structural formulae I-III are crystalline.
The crystalline amine salts of structural formula I exhibit greater chemical and physical stability than the parent zwitterionic compound of structural formula (IV) below. These salts are therefore more desirable for the preparation of solid pharmaceutical dosage forms containing the pharmacologically active ingredient.
The amine salts of the present invention, which exhibit potent integrin xcex1vxcex23 antagonist activity, are particularly useful for inhibiting bone resorption, treating and/or preventing osteoporosis, and inhibiting vascular restenosis, diabetic retinopathy, macular degeneration, atherosclerosis, inflammatory arthritis, cancer, and metastatic tumor growth.
Another aspect of the present invention provides compounds 2-6a and 2-6b in the form of a zwitterion trihydrate.